1,3,6-substituted 5-halouracils

ABSTRACT

1,3,6-SUBSTITUTED 5-HALOURACILS OF THE FORMULA 1-R1,2,4-DI(O=),3-R3,5-X,6-CH3-1,2,3,4-TETRAHYDROPYRIMIDINE WHEREIN X IS HALOGEN, ONE OF R1 AND R3 IS SATURATED OR UNSATURATED LOWER ALKYL AND THE OTHER OF R1 AND R3 IS 4-R-PHENYL , PHENYL-(CH2)M- OR -CH&lt;(-(CH2)N-) WHEREIN R IS HYDROGEN, LOWER ALKYL, LOWER ALKOXY, OR HALOGEN; M IS 1 OR 2; AND N IS AN INTEGER OF 4 OR 5; PROVIDED THAT R3 IS OTHER THAN CYCLOLHEXYL. THESE COMPOUNDS ARE USEFUL AS INTERMEDIATES IN THE PRODUCTION OF THE CORRESPONDING 5-AMINO DERIVATIVES WHICH ARE PHARMACEUTICAL AGENTS. THE 5-HALOURACILS ARE PREPARED BY HALOGENATING 1,3,6-SUBSTITUTED URACILS OF THE FORMULA 1-R1,2,4-DI(O=),3-R3,6-CH3-1,2,3,4-TETRAHYDROPYRIMIDINE WHEREIN ONE OF A1 AND A3 IS HYDROGEN AND THE OTHER OF A1 AND A3 IS 4-R-PHENYL, PHENYL-(CH2)M- OR -CH&lt;(-(CH2)N-) PROVIDED THAT A3 IS OTHER THAN CYCLOLHEXYL.

United States Patent 3,711,483 1,3,6-SUBSTITUTED S-HALOURACILS Shigeo Senda, 30 Nikkocho-Z-chome, Gifu, Japan No Drawing. Filed Apr. 16, 1970, Ser. No. 29,241 Claims priority, application Japan, Apr. 19, 1969, 44/250,531; May 29, 1969, 44/ 42,428 Int. Cl. 007d 51/30 US. Cl. 260-260 8 Claims ABSTRACT OF THE DISCLOSURE 1,3,6-substituted S-halouracils of the formula wherein R is hydrogen, lower alkyl, lower alkoxy, or halogen; m is 1 or 2; and n is an integer of 4 or provided that R is other than cyclohexyl. These compounds are useful as intermediates in the production of the corresponding S-amino derivatives which are pharmaceutical agents. The S-halouracils are prepared by halogenating 1,3,6-substituted uracils of the formula R1 CHa wherein one of A and A is hydrogen and the other of A and A is provided that A is other than cyclohexyl.

This invention relates to novel 1,3,6-substituted S-halouracils and to a method for their production.

The novel 1,3,6-substituted S-halouracils of the invention have the following general formula:

wherein X is halogen, one of R and R is and the other of R and R is saturated or unsaturated lower alkyl, R is hydrogen, lower alkyl, lower alkoxy, or halogen; m is 1 or 2; and n is 4 or 5; provided that R is other than cyclohexyl.

In this invention, the halogen may be, for example, chlorine, bromine, or iodine; the saturated or unsaturated lower alkyl may be, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, or allyl; and the lower alkoxy may be, for example, methoxy or ethoxy. The terms lower alkyl and lower alk oxy are intended to include alkyl moieties of 1-6 carbon atoms.

3,711,483 Patented Jan. 16, 1973 The novel compounds of the invention afford a series of compounds exhibiting analgesic, antipyretic, and antiinfiammatory action when the halogen atom is substituted by ammonia or monoalkylamines, dialkylamines or cyclic amines. Thus the compounds of the present invention are useful as intermediates for the manufacture of the pharmaceutical agents disclosed in my copending application Ser. No. 29,240, filed April 16, 1970, entitled 1,3,6-Substituted S-Aminouracil and Derivatives Thereof and Their Production.

The novel compounds of the invention can be manufactured, for example, by the reaction of 1,3,6-substituted uracils of the formula (where R and R are the same as above) with a halogenation agent so that a halogen atom is introduced into the 5-position.

All conventional halogenation agents are advantageously used in this method; such as free halogen, a solution of free halogen (in, for example, acetic acid), hydrogen halide (or its salt) with hypohalite (or its salt), phosphorus halide, sulfuryl halide, N-halosuccinic imide, N-haloacetamide, etc. The use of free halogen is, however, most preferred. In the case of iodination, addition of oxidizers, such as nitric acid, hydrogen peroxide, etc., to the halogenation agent is advantageous.

Any kind of solvent may be used in the halogenation reaction, provided that said solvent does not inhibit the halogenation. Examples of such solvents are acetic acid, acetic anhydride, chloroform, carbon tetrachloride, benzene, toluene, etc. When free halogen is used as a halogenation agent, the use of glacial acetic acid, chloroform, or methanol is desired. The halogenation reaction is, in general, carried out with or without cooling, or at room temperature, or with heating in order to accelerate the reaction. In the halogenation reaction, such acid removers as alkali carbonate, alkali bicarbonate, alkali hydroxide, etc. may be added, if desired, to remove the hydrogen halide produced during the reaction. Thus, according to the kind of halogenation agent used, halogens such as chlorine,

. bromine, iodine, etc. are introduced at the 5-position of the uracil nucleus, and the compounds of the invention are obtained.

This invention is illustrated by the following examples.

EXAMPLE 1 S-bromo-1,6-dimethyl-3-phenyluracil EXAMPLE 2 5-chloro-l,6-dimethyl-3-phenyluracil Concentrated hydrochloric acid (2.2'ml.) was added to a suspension of 6.7 g. of 1,6-dimethyl-3-phenyluracil in acetic anhydride, and then 11 ml. of 10% aqueous solution of sodium hypochlorite was gradually added thereto. The reaction mixture was allowed to stand for 3 hours while cooling to below 60 C. when the reaction solution 3 became hot. The reaction solution was poured over 300 g. of ice water, and the separated mass was collected, washed with Water, and recrystallized from ligroin to give colorless needles, M.P. 156-8 C.

Analysis.Calculated for C H O N Cl (percent): C, 57.50; H, 4.43; N, 11.16. Found (percent): C, 57.22; H, 4.41; N, 10.99.

EXAMPLE 3 S-iodo-1,6-dimethy1-3-phenyluracil 1,6-dimethyl-3-phenyluracil (6.6 g.) was dissolved in 200 ml. of glacialacetic acid. First, 4 g. of iodine were added to the solution and then 15 drops of concentrated nitric acid were gradually added during about 2 hours. After the color of iodine disappeared, 500 ml. of water were added with stirring and the mixture was allowed to stand. The separated mass was collected, washed with water, and recrystallized from methanol to give colorless needles, M.P. 233-4 C.

Analysis.Calculated for C H O N I (percent): C, 42.10; H, 3.24; N, 8.18. Found (percent): C, 42.12; H, 3.33; N, 8.09.

Similarly prepared were the following compounds in accordance with the method disclosed in Examples 1, 2 and 3.

S-bromo-1-allyl-6-methyl-3-phenyluracil To ml. of 10% aqueous sodium hydroxide solution were added 15 g. of 5-bromo-6-methyl-3-phenyluracil, 8 g. of allyl bromide, and 30 m1. of ethanol, and the mixture was heated on a steam bath for 5 hours. Ethanol was removed from the mixture, and in vacuo the residue collected, washed with water, and recrystallized from ethanolwater to give colorless needles, M.P. 136 C.

Analysis.-Calculated for C H O N Br (percent): C, 52.38; H, 4.08; N, 8.72. Found (percent): C, 52.56; H, 4.15; N, 8.51.

Example Oyclopent 1 Math Reerystn. solvent, Appearance M.P. C.)

Methanol Nee Novel compounds according to this invention may also be manufactured by alkylating a 5-halo-6-methyluracil derivative having the formula A (II) in which X is halogen and one of A and A is hydrogen and the other of A and A is wherein R, m and n are as defined above; provided that A is other than cyclohexyl.

In carrying out the alkylation reaction, various kinds of alkylating agents may be used. For example, it is preferred to use various kinds of saturated or unsaturated alkyl halides as well as saturated or unsaturated alkyl sulfates. Examples of such alkylating agents are allyl bromide, isopropyl bromide, butyl bromide, dimethyl sulfate, diethyl sulfate, etc. .They are, of course, given for the purpose of illustration only and the present invention is not limited to the use of the above alkylating agents only. The alkyl moiety of the alkylation agent is saturated or unsaturated lower alkyl.

In carrying out the alkylation reaction, it is preferred to use water as a solvent or organic solvents, such as methanol, ethanol, acetone, or benzene, and to use simultaneously such condensation agents as inorganic bases EXAMPLE 23 S-bromo-1,6-dimethyl-3-phenyluracil To ml. of 5% aqueous sodium hydroxide solution was added 25 g. of 5-bromo-6-methyl-3-phenyluracil. 14 g. of dimethyl sulfate were gradually added to the mixture dropwise with stirring. The mixture was allowed to react at room temperature for 2 hours and was then heated on a steam bath for 30 minutes, after which a precipitate was collected, washed with water, and recrystallized from methanol to give colorless prisms, M.P. 198 C.

Analysis.-Calculated for C H O N Br (percent): C, 48.82; H, 3.76; N, 9.47. Found (percent): C. 48.80; H, 3.86; N, 9.22.

EXAMPLE 24 5-bromo-1-butyl-6-methyl-3 -phenyluracil To 30 ml. of 10% aqueous sodium hydroxide solution was added 15 g. of S-bromo 6 methyl-3-phenyluracil. The mixture was stirred on a steam bath for 5 hours together with 10 g. of butyl bromide and 60 ml. of ethanol. Ethanol was removed in vacuo, and the residue collected, washed with water, and recrystallized from ligroin to give colorless needles, M.P. 111 C.

Analysis-Calculated for C H O N Br (percent): C, 53.45; H, 5.09; N, 8.31. Found (percent): C, 52.91; H, 5.00; N, 8.16.

EXAMPLE 25 wherein X is halogen; R is saturated or unsaturated 5-brorno-3-isopropyl-6-methyll-phenyluracil lower and R1 13 To 30 ml. of aqueous sodium hydroxide solution m was added g. of 5-bromo-6-methyl-l-phenyluracil. The mixture was stirred for 5 hours on a steam bath together 5 with 10 g. of isopropyl bromide and 60 ml. of ethanol. wherein R is hydrogen, lower alkyl, lower alkoxy, or Ethanol was removed in vacuo, and the residue collected, halogen provided that when R is hydrogen or chloro and washed with water, and recrystallized from methanol to X is chloro or bromo, R is other than methyl. give colorless needles, M.P'. 230 C. 2. The compound according to claim 1, being S-bromo- Analysis.-Ca1culated for C H O N Br (percent): C, 10 3-ethy1-6-methyl-l-phenyluracil.

52.08; H, 4.68; N, 8.67. Found (percent): C, 52.26; H, 3. The compound according to claim 1, being S-bromo- 4.70; N, 8.41. 3-isopropyl-6-methyl-l-phenyluracil.

Using the procedures of Examples 2225, the follow- 4. The compound according to claim 1, being 5-bromoing compounds were prepared: 3-butyl-6-methyl-l-phenyluracil.

Recrystn. solvent Appearance M.P.( C.)

Methanol Needles... 165 do 156-8 233-4 135 117 238 232 do.. 216 do 207-9 Methanol-HzO 127 01 175 245 209 259 174 240 15s The 1,3,6-substituted uracils of the formula 5. The compound according to claim 1, being 5-bromo- R1 3-allyl-6-methyl-l-phenyluracil. 6. The compound according to claim 1, being 5-bromo- 3,6-dimethy1-l-p-tolyluracil.

N 7. The compound according to claim 1, being S-bromo- I; 3,6-dimethyl-l-p-methoxyphenyluracil.

Ra 8. The compound according to claim 1, being S-iodowhich are halogenated to form the 5-halouracils of the 3,6-dimethyl-l-phenyluracil. present invention can be prepared by reacting ethyl acetoaceta-te or diketene with a urea of the formula rences Cited R'NHCQNHIQ, where R and R are as defined above. UNITED STATES PATENTS x g g i gfifg the formula, 3,235,363 2/1966 Luckenbaugh et al. 260-260 CH3 FOREIGN PATENTS 106,253 4/1967 Denmark 260260 X- =0 H N ALTON D. ROLLINS, Primary Examiner 0 A. T. TIGHE, Assistant Examiner 

